The concept that plasma lipoproteins can regulate cellular activation and proliferation is well established. Among the numerous regulatory phenomena that are mediated by either native or modified lipoproteins is the suppression of lymphocyte function. A biologically active moiety of the immunosuppressive lipoprotein, LDL-In, that possesses regulatory activity characteristic of the native lipoprotein, has been identified as apoprotein (apo) E. Apo E is also one of the major proteins synthesized and secreted by human monocytes. This synthesis is enhanced by plasma lipoprotein-induced cholesteryl ester loading and inhibited by immunologic activation of the monocyte. An essential biological theme of the immune response is the use of cellular collaboration via the synthesis of soluble effector molecules to regulate specific responses to relevant stimuli. Therefore, it is both timely and pertinent to investigate the relationship between the biological properties of monocyte-secreted apo E and plasma lipoprotein-associated apo E. The major objective of this proposal is to examine the hypothesis that a regulatory network involving monocyte-derived apo E exists betwen lymphocytes and monocytes. This hypothesis will be examined by pursuing three specific aims. The first specific aim is to determine if monocytesecreted apo E has the capacity to inhibit lymphocyte function and that it has the biological characteristics of plasma lipoprotein-derived apo E. The second aim is to understand the role played by monocyte apo E in the phenomenon of lipoprotein-mediated inhibition of lymphocyte function by identifying what factors influence the amount of apo E secreted by monocytes including the roles played by plasma lipoprotein-induced cholesterol ester loading and various immunologic stimuli including lymphokines. Finally, the fate of monocytesecreted apo E will be studied to identify if it interacts directly with lymphocytes or indirectly via the formation of stable lipoproteins, and to characterize biologically significant interactions of apo E with lymphocytes.